Pretreatment Levels of Soluble Tumor Necrosis Factor Receptor 1 and Hepatocyte Growth Factor Predict Toxicity and Overall Survival After⁹⁰Y Radioembolization: Potential Novel Application of Biomarkers for Personalized Management of Hepatotoxicity

Abstract

Liver function may be negatively affected by radiation for treatment of hepatic malignancy.Pretreatment blood cytokine levels are biomarkers for prediction of toxicity and survival after external beam radiation therapy. We hypothesized that cytokines may also predict outcomes after radioembolization, enabling a biomarker-driven personalized approach to treatment. Methods: Pre-therapy blood samples from patients enrolled on a prospective protocol evaluating 90 Y radioembolization for management of intrahepatic malignancy were analyzed for two cytokines selected based on prior studies in stereotactic body radiotherapy (SBRT), soluble tumor necrosis factor receptor 1 (sTNFR1) and hepatocyte growth factor (HGF), via enzymelinked immunosorbent assay (ELISA), and key dosimetric parameters were derived from posttreatment 90 Y PET/CT imaging. Toxicity was defined as a change in albumin-bilirubin score (ALBI) from baseline to follow up [3-6-month post-treatment (ΔALBI)]. Associations of cytokine levels, dose metrics, and baseline liver function with toxicity and overall survival were assessed. Results: Data from 43 patients treated with 90 Y radioembolization for primary [48.8% (21/43)] or secondary [51.2% (22/43)] malignancy were assessed. Examined dose metrics and baseline liver function were not associated with liver toxicity; however, levels of sTNFR1 (p=0.045) andHGF (p=0.005) were associated with liver toxicity in univariate models. Cytokines were the only predictors of toxicity in multivariable models including dose metrics and prior liver directed therapy. sTNFR1 (HR 12.3; p<0.001) and HGF (HR 7.5; p<0.001) predicted overall survival, and findings were similar when models were controlled for absorbed dose and presence of metastatic disease. Conclusions: Pretreatment cytokine levels predict liver toxicity and overall survival. These pathways can be targeted with available drugs, an advantage over previously studied dose metrics and liver function tests. Interventions directed at the TNF alpha axis should be considered in future studies for prevention of liver toxicity, and HGF should be explored further to determine whether its elevation drives toxicity or indicates ongoing liver regeneration after prior injury.

Biomarker-driven molecular imaging probes in radiotherapy

“…Several serum biomarkers and urine biomarkers have been evaluated for early and accurate assessment of radiation-induced toxicity 168 , 174 , 175 , but failed to locate the toxicity origins. To this end, early imaging biomarkers for a specific manifestation are actively screened to achieve monitoring of a spatiotemporal toxicity profile.…”